Abstract 1142: Activity and tolerability of combination of trastuzumab deruxtecan with the next generation PARP1-selective inhibitor AZD5305 in preclinical models
Authors: Yann Wallez, Theresa Proia, Elisabetta Leo, Laura Bradshaw, Zena Wilson, Joe’l Owusu, Azadeh Cheraghchi-Bashi-Astaneh, Anna Staniszewska, Mark O’Connor, Sabina Cosulich, Jerome Mettetal
Journal: Cancer Research (2022)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor, approved for HER2+ metastatic breast cancer. Clinically, T-DXd has demonstrated antitumor activity in both HER2+ and HER2-low cancers. Due to the role of PARP1 in resolution of DNA damage induced by topoisomerase I trapping, we tested the combination of the next generation PARP1-selective inhibitor AZD5305 with T-DXd. Methods: We evaluated the antiproliferative ability of the combination of T-DXd with AZD5305 in a panel of 27 breast cancer cell lines in an in vitro 7-day viability assay. The combination was also evaluated in vivo in two non-HRD HER2+ models, KPL4 (Breast) and NCI-N87 (Gastric) at doses of 3mg/kg and 10mg/kg Q3W for T-DXd combined with 0.01, 0.1, and 1 mg/kg QD of AZD5305. To evaluate the specificity of the combination activity in tumor cells (vs normal tissue), we further evaluated the combination in a human 2D in vitro bone marrow progenitor assay. Results: We found that the combination had enhanced in vitro cell killing activity over single agents in 8/27 of the models tested. The benefit was present in both Homologous Recombination Deficient (HRD) as well as Homologous Recombination proficient, suggesting it does not depend on HRD (as defined by mutations in DNA damage repair genes). Mechanistically, T-DXd activated PARP and the combination of T-DXd with AZD5305 abrogated PARP1 auto-parylation, leading to enhanced DNA damage (gH2AX, pRPA-S4/8) and cell death (cCasp3). In vivo, the combination was well tolerated and more active than monotherapy of either compound in both KPL4 (at 30 days the growth inhibition was 95% at 10mg/kg T-DXd, 10% at 1mg/kg AZD5305, and 100% TGI with 97% regression with T-DXd + AZD5305) and NCI-N87 (at 41 days TGI of 74% with 10mg/kg T-DXd, 47% with 1mg/kg AZD5305, and 100% TGI with 40% regression for T-DXd + AZD5305; p&amp;lt;0.0001). In an in vitro human bone marrow assay, the combination demonstrated modest enhancement over monotherapy activity (average Loewe Synergy Score of 3.1). We tested alternative doses and schedules of the combination in KPL4 in vivo. We found that reducing the dose of AZD5305 as low as 0.01mg/kg resulted in combination benefit (100% TGI with 78% regression for combination versus 0% TGI for monotherapy on day 30). Further, 7-day delay of 0.01mg/kg AZD5305 in combination with 10mg/kg T-DXd also provided greater activity (&amp;gt;100% TGI with 72% regression on day 30) vs. monotherapy T-DXd alone (95% TGI). Conclusions: These results suggest that T-DXd combined with the next generation PARP1 inhibitor AZD5305 is a potentially active combination, with preclinical activity demonstrated in HRD and HR proficient models. Further, the dose and scheduling may warrant exploration clinically to optimize therapeutic index. Citation Format: Yann Wallez, Theresa Proia, Elisabetta Leo, Laura Bradshaw, Zena Wilson, Joe’l Owusu, Azadeh Cheraghchi-Bashi-Astaneh, Anna Staniszewska, Mark O’Connor, Sabina Cosulich, Jerome Mettetal. Activity and tolerability of combination of trastuzumab deruxtecan with the next generation PARP1-selective inhibitor AZD5305 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1142.